- defeciency in homogentistic acid oxydase

Alkaptonuria

(can't break down tyrosine)

- findings: dark urine after it sits for a while, hyperpigmented sclera, dark connective tissue, arthralgias

alkoptonuria

(can'tbreak down tyrosine)

- findings: mental retardation, short stature, fair skin, musty body odor

phenylketonuria

(can't break down Phe)

- causes of phenylketonuria (2)

1. def of phenylalanine hydroxylase

2. Def of THB cofactor

3 causes of albinism

1. failure of neural crest to migrate

2. Tyrosinase def.

3. defective tyrosine trasporters

Describe how you get cysteine from methionine

met --> (homocysteine methyl transferase + SAM) --> homocysteine --> (cystathioen synthase + B6) --> cystathione --> cysteine

how do you get homocysteine to make methionine?

signs of homocysteinuria

- tall stature, lens subluxation, mental retardation, osteoporosis, kyphosis

- high levels of homocysteine in urine

what causes cysteinuria?

- Defect in proximal tubule, cant absorb COLA

- COLA: cysteine, orthithine, lysine, arginine

- leads to kidney stones

how to treat cysteinuria?

what is cause of maple syrup urine disease? enzyme?

- can't degrade branched amino acids (Ile, Leu, Val)

- alpha-ketoacid dehydrogenase

AR disease that can lead to pellagra

Hartnup dz: excretion of trptophan, so can't make niacin

- cause: def. of G6PD

- liver can't produce glucose forbody

- signs: severe hypoglycemia, increased glycogen in liver --> hepatosplenomegaly, increased blood lactate

- def. of lysosomal a-1,4-glucosidase

- cardiomegaly and early death

- Debranching enzyme def.

- milder form of Von geirke's

- normal sized liver

- skeletal muscle glycogen phosphorylase

- increased glycogen in muscle, fatigue and myoglobinuria with extreme exercise, muscle cramps

a-galactosidase-A def?

Fabry's (XR)

(ceramide thihexoside accum.)

Beta-glucocerebroside def?

Gaucher's disease

(glucocerebroside accum.)

Neimann-Pick

(Sphingomyelin accum.)

Tay-sachs

(GM2 ganglioside accum)

Neiman pick: hepatosplenomegaly, foam cells

Taysach: no hepatosplenomegaly, lysosomes with onion skin

Krabbe's

(galactocerebroside accum)

Metachromatic leukodystrophy

(cerebroside sulfate accum.)

Hurler's syndrome

(heparan sulfate, dermatan sulfate accum)

Iduronate sulfatase def?

Hunters

(heparan sulfate, dematan sulfate accum)

hunters

XR

classic galactosemia

(def. in galactose-1-P uryltransferase)

Fructose intolerance:

hypoglycemia, jaundice, cirrhosis, vomitting

rate limiting step in heme synthesis

(siderblastic anemia)

def of porphobilinogen deaminase

accum of porphobilinogen and d-ALA

5 P's

painful abdomen, pink urine, polyneuropathy, psych disturbs, precipitated by drugs

TX: glucose and heme, inhibit ALA synthase

what is porphria cutanea tarda?

def in uroporphyrinogen decarboxylase

uroporphyrin accum

tea colored urine

blistering cutaneous photosensitivity

most common

lead poisoning?

def in ferrochelatase and ALA dehydrate

accum protoporphyrin

lead lines on gums and epiphyses of long bones, abdominal colic, siderblastic anemia, drops, encephalopathy, stippling

Tx: adults: Dimercaprol and EDTA, kids: succimer

glycine, aspartate, glutamine

2 carbons fromTHF

Rate limiting step of pyrimidine synthesis

whats it require

Carbamoyl phosphate synthase-2 = enzyme

requires: aspartate, glutamine, ATP, CO2

1. Defect urea cycle: ornithine transcarbamoylase (OTC) def. presents with hyperammoniemia

2. inability to synthesize UMP from orotic acid, megaloblastic anemia not better with folate or B12, no hyperammonemia, treat with uridine

ribonucleotide reductase

(blocked by hydroxyurea)

Lisch-Nehan syndrome

absence of HGPRT enzyme

can't recover nucleotides, broken down instead, excess uric acid production

transition = same type nucleotide sub

tranversion =pruine for pyrimidine and vice versa

mutations types

4

silent - 3rd position, same aa

missense - change in aa, but similar

nonsense - early stop codon

frame shift

cant repair thymine dimers from UV damage

defect in nucleotide excision repair

DNA synth 5-->3

RNA synth 5-->3

RNA read 3-->5

protein synth N --> C

rRNA is most abundant, made in nucleolus

mRNA is the longest

tRNA is the smallest of the 3

glucose absense = CAP binding protein attaches (promoter)

lactose present = repressor removed

both needed for production of enzyme

tRNA + correct AA + ATP

enzyme is aminoacyl-tRNA transferase

inhibit 50S peptidyltransferase

(streptogramin does too)

elongation factor-2

allows mRNA to twerk

diptheria and Clos. difficile block EF-2

failure of addition of M-6-Phosphate to proteins in golgi so they dont end up in the lysosome but are sent outside the cell

-coarse facial features, clouded corneas, restricted joint movment, high plasma levels of lysosomalenzymes. often fatal

Chediak-Higashi dz

defect in polymerization of microtubules --> leadse to decrease in phagocytosis

kartagener's sundrome

defect in dynein --> immobilecilia

connective tissue

sarcomas

muscle

sarcomas

1 - bone, skin, tendon, cornea, late wound repair

2- cartillage, vitreous body, nucleus pulposus

3- reticulin,  blood vessels, uterus, fetal tissue, granulation tissue

4- basement membrane

1. made in rough ER (Gly-X-Y, where X is lysine or proline or hydroxyproline)

2. Hydroxilated using vit C

3. glycosylated forming procollagen = triple helix of three alphas

4. exocytoses thru golgi

5. outside cell - cleavage of terminal regions of procollagen --> tropocollagen

6. lysyl oxidase links lysine-hydroxylisine bonds to make collagen

Ehlers-danlos

defect in collagen synthesis

type 3 most frequently affected

assoc with berry aneurysm, organ rupture

multiple fractures

blue sclera

sometimes hearing loss (abnormal middle ear)

dental imperfections due to lack of dentin

AD is most common

alports

defect in type 4 collagen

X-linked recessive

slpit basement membrane in kidney

chrom 15

deletion of normally active paternal gene

retardation, hyperphagia, hypogonadism, hypotonia

chrom 15

deletion of normally active mama allele

mental retardation, seizures, ataxia, inappropriate laughter

FGF-receptor 3

assoc w advanced paternal age

APKD1 gene, chrom 16

AD

assoc with berry aneurisms, mitral valve prolapse, always bilateral

APC gene deletion on chrom 5

AD

always leads to colon cancer

CAG repeat on chrom 4

decreased GABA and ACh

caudate atrophy

fibrillin gene mutation on chrom 15

assoc with cystic medial necrosis of aorta, aortic dissection, aortic incompetence, mitral valve is floppy

AD assoc with RET gene

1- pituartaty, pancreas, parathyroid

2a - parathyroid, pheos, medullary thyroid

2b- pheos, medullary thyroid

NF1 gene on chrom 17, AD

cafe-au-lait spots, lisch nodules, scoliosis, optic gliomas, pheos

NF2 gene, chrom 22, AD

bilateral acoustic neuromas

VHL gene, chrom 3, AD

activates HIF = transcription factor

also activates angiogenic growth factors

hemangioblastomas of retina, cerebellum

50% develop multpiple bilaterla renal cell carcinomas

A, D, E, K

toxicity more common than with water soluble

Deficiency in this vitamin results in night blindness and dry skin

Excess in this vitamin causes joint pain, headaches, alopecia, dry skin

It is also a teratogen

Thiamine

1. pyruvate dehydrogenase

2. alpha ketoglutarate dehydrogenase

3.  transketolase (HMP shunt)

4. Branched Chain AA dehydrogenase

1. impaired glucose breakdown

2. wernicke-korsakoff

3. wet berri berri (dilated cardiomyopahty)

4. dry berriberri (polyneuropathy) -muscle wasting

Riboflavin -FADH2

Red-ox reactions

1. Cheliosis

2. corneal vascularizatoin

Constituent of NAD, NADP+

derived from tryptophan

requires B6 for synthesis

Deficiency causes

1. glossitis

2. Pellagra

Excess causes flushing

1. decreased tryptophan absorption (hartnup disease)

2. malignant carcninoid syndrome (increased trytophan metabolism)

3. INH (decreased B6 which is necessary for B3 synthesis)

Essential component of CoA

which is needed for fatty acid synthase

1. synthesis of niacin from tryptophan

2. transaminations (AST, ALT)

3. decarboxylation rxns

4. glycogen phosphorylase

5. cystathione synthesis

6. heme synthesis

Deficiency can cause:

1.  macrocytic, megaloblastic anemia

2. hypersegmented PMNs

3. neurologic symptoms (paresthesias from subacute combined degeneration)

Deficiency usually takes several years of malabsorption and can be cuase by:

1. Diphylllobothrium latum

2. lack of intrinsic factor

3. absence of terminal illeum (chrons)

deficiency can result in a macrocytic megaloblastic anemia without neurologic symptoms.

seen in alcoholism and pregnancy

1. transfers methyl units

2. important oin the regeneration of methionine (also requires B12)

3. converts NE to Epinephrine

1.  pyruvate carboxylase (pyruvate to -> oxaloacetate) gluconeogenesis

2. acetyl CoA carboxylase (acetyl CoA -> malonyl CoA) fatty acid synthesis

3.  propionyl CoA to methylmalonyl CoA (odd chain b-oxidation of fatty acids)

Antioxidant that protects erythrocytes and membranes from free radical damage

a deficiency causes  increased fragility of RBCs causing hemolytic anemia

enzyme that neonates lack that is critical for gamma carboxylation of blod clotting factors 2, 7, 9, 10, protein c, s

vitamin K

(must give neonates an injection)

deficiency would increase PT and PTT

bacteria normally synthesize it (newborns dont have GI bacteria yet)

Essential for the activity of 100+ enzymes

important in the formation of ____ fingers (transcription factor)

lack causes: delayed wound helaing, decreased adult hair

why does excessive ethanol intake increase the amount of:

1. pyruvate converted to lactate

2. oxaloacetate converted to malate

thereby inhibiting gluconeogenesis and causing hypoglycemia

in what compartment do the follwing pathways occur:

1. glycolysis

2. fatty acid synthesis

3. HMP shunt,

4. protein and steroid synth

Heme synth

urea cycle

gluconeogenesis

CFTR gene

misfolded protein, degraded before reaching cell surface

high Cl- in sweat

macro-orchidism, long face and large jaw, large ears, autism,mitral valve prolapse with MR?

Fragile X

FMR1 gene

CGC

Trinucleotide repeats

Huntington CAG

Myotonic: CTG

Fragile X: CGC

Freidrichs: GAA

trisomy 18

MR, rocker bottom feet, small jaws, clenched hands

trisomy 13

MR, rockerbottom feet, cleft lip/palate, holoproencephaly, microceph, small eyes,

peri involves centromere and can proceed thru meiosis

both may deecrease fertility

cri du chat

microdeletion of 5p

mild MR, microbrain, epicanthal folds, cardiac abnorms

williams syndrome

MR, hypercalcemia, good verbal skills, cardiovascular problems

role of vit C?

1. collagen

2. Dop --> NE

3. absorption of iron

anabolic processes

resp. burst

p450

glutathione reductase

enzyme: PFK-1

+ = AMP, F-2,6-BP

- = ATP, citrate

enzyme: pyruvate kinase

+ = F-1,6-P

- = AMTP, alanine

things that twerk on enzyme that makes Acteyl coA? what are co factors?

enzyme: pyruvate decarboxylase

Cofactors: B1, B2, B3, B5, lipoic acid

+ = ADP, Ca2+, NAD/NADH ratio

- = ATP, NADH, Acetyl-coA

fructose bisphosphatase 2 v. PFK2?

PFK in fed state makes F-2,6-P

other one breaks down f-2,6-P in fasting state

effects of insulin v. glucogon on cAMP?

insulin decrease cAMP, glucagon increase cAMP

increase cAMP increases PKA and activates FBPase2 and inactivates PFK2

hemolytic anemia

pyruvate kinase involved 95%

inhibits lipoic acid involved in pyruvate decarboxylase

results in rice water stools, vomit, garlic breath

moves lactate from muscle to liver, liver makes pyruvate out of lactate and send it back

costs like 4 ATPs

things that inhibit ETC?

causes increase heat

2,4-DNP, aspirin, thermogenin

locations of gluconeogenesis enzymes

(4)?

pyruvate carbox - mito

PEP carboxykinase - cytosol

F-16-BPase cytosol

G6Pase RER

types of fatty acid chains used in gluconeogenesis?

ODD chains, not even chains

odd chains yield propionyl-coA

enters TCA as succinyl coA goes on to gluconeogenensis

candiasis, Kelb, ASpergilis, E.coli

(CAKES)

detoxifies free radicals and peroxides

need G6PD to maintian NADPH levels to keep regenerating Glutathione

FI is due to aldolase B def. Fructose-1-p acummulates in cells and takes up all P's. AR. jaundice, hypoG, cirrhosis, vomiting

EFuria defect in fructokinase. fructose can get into cell. lots of it in urine

essential amino acids pneuomic?

PVT TIM HALL

ile, leu, phe, valine, thr,trp, met, his, arg, lys, val

treatment of hyperammonemia?

benzoate or phenylbutarate: bind AA's for exretion and reduce NH4 levels

lactulose: traps NH4 in gut bc of acidic pH

TRP derivatives?

niacin (via B6)

or

Serotonin (via B4) > Melatonin

GABA (via B6)

or

Glutathoine

breakdown products of

1. Dopamine

2. NE

3. Epi

1. HVA

2. VMA

3. metanephrine

think carnitine def.

cant get LCFAs into mito results in tox accumulation

HMG coA synthase = ketogenesis

HMG coA reductase = cholesterol synth.